JAC Advance Access originally published online on August 5, 2006
Journal of Antimicrobial Chemotherapy 2006 58(4):714-722; doi:10.1093/jac/dkl306
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Specific mutations in HIV-1 gp41 are associated with immunological success in HIV-1-infected patients receiving enfuvirtide treatment
1 Department of Experimental Medicine and Biochemical Sciences, University of Rome ‘Tor Vergata’, Rome, Italy 2 Department of Pharmaco-Biology, University of Calabria Cosenza, Italy 3 National Institute for Infectious Diseases ‘L. Spallanzani’, Rome, Italy 4 Clinic of Infectious Diseases, University of Turin, Hospital ‘Amedeo di Savoia’ Turin, Italy 5 Hospital ‘SM Annunziata’ Florence, Italy
Received 20 March 2006; returned 30 May 2006; revised 4 July 2006; accepted 6 July 2006
*Correspondence address. Department of Experimental Medicine and Biochemical Sciences, University of Rome ‘Tor Vergata’, Via Montpellier 1, 00133 Rome, Italy. Tel: +39-06-7259-6553; Fax: +39-06-7259-6039; E-mail: aquaro{at}uniroma2.it
Objectives: To investigate gp41 variability and correlation with viro-immunological parameters in 54 HIV-1-infected patients receiving enfuvirtide added as single active drug to a failing regimen.
Methods: One hundred and two HIV-1 gp41 sequences and clinical follow-up from 54 enfuvirtide-treated patients were analysed from baseline to week 36 of treatment. The association of mutations with viraemia/CD4 count was assessed by Mann–Whitney test.
Results: The addition of enfuvirtide to the failing regimen induced at week 4 a viraemia decrease from 5.1 to 4.3 log10/mL (P = 0.0002) and a CD4 increase from 48 to 106 cells/mm3 (P = 0.008). While viraemia rebounded to 4.8 and 4.6 log10/mL at week 12 and 36, respectively, CD4 continued to increase to 136 cells/mm3 at week 36. Enfuvirtide resistance mutations, rarely found at baseline, occurred in 45/54 (83.3%) enfuvirtide-treated patients. V38A/E were the most represented mutations at all time-points. The presence of V38A/E was significantly associated with a 4.5-fold CD4 increase from baseline to week 24 and with a 6-fold increase at week 36 (P = 0.004 and 0.02 compared without V38A/E, respectively), without significant correlation with viraemia. In contrast, Q40H + L45M (present in six enfuvirtide-treated patients at week 36) correlated with CD4 loss from baseline to week 36 (P = 0.02), without significant correlation with viraemia. Mutation N126K (observed in six enfuvirtide-treated patients, never found at baseline) abrogates the fourth gp41 glycosylation site and correlates with a 2.1-fold CD4 increase at week 24.
Conclusions: Specific enfuvirtide resistance mutations (V38A/E) are associated with a sustained CD4 increase, without remarkable effects upon viraemia. This CD4 recovery, due to virus- and immune-mediated mechanisms most probably not applicable to protease/reverse transcriptase inhibitors, is important for innovative therapeutic strategies.
Keywords: resistance , CD4 cell counts , viraemia , glycosylation
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  D. Eggink, C. E. Baldwin, Y. Deng, J. P. M. Langedijk, M. Lu, R. W. Sanders, and B. Berkhout Selection of T1249-Resistant Human Immunodeficiency Virus Type 1 Variants J. Virol., July 1, 2008; 82(13): 6678 - 6688. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Descamps, L. Assoumou, B. Masquelier, A.-G. Marcelin, S. Saidi, C. Tamalet, J. Cottalorda, J.-C. Plantier, B. Montes, J. Izopet, et al. HIV-1-infected patients from the French National Observatory experiencing virological failure while receiving enfuvirtide J. Antimicrob. Chemother., June 13, 2008; (2008) dkn225v1. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Saberi, N. H Caswell, C. I Gruta, J. N Tokumoto, and B. J Dong Immunologic Benefits of Enfuvirtide in Patients Enrolled in a Drug Assistance Program Ann. Pharmacother., May 1, 2008; 42(5): 621 - 626. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Chinnadurai, D. Rajan, J. Munch, and F. Kirchhoff Human Immunodeficiency Virus Type 1 Variants Resistant to First- and Second-Version Fusion Inhibitors and Cytopathic in Ex Vivo Human Lymphoid Tissue J. Virol., June 15, 2007; 81(12): 6563 - 6572. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Garg, A. Joshi, E. O. Freed, and R. Blumenthal Site-specific Mutations in HIV-1 gp41 Reveal a Correlation between HIV-1-mediated Bystander Apoptosis and Fusion/Hemifusion J. Biol. Chem., June 8, 2007; 282(23): 16899 - 16906. [Abstract] [Full Text] [PDF]
|
|